Yao Lihang, Jenkins Katie, Horn Paul S, Lichtenberg M Hayden, Woollett Laura A
Department of Pathology and Laboratory Medicine, 2180 E. Galbraith Rd, Genome Research Institute, University of Cincinnati Medical Center, Cincinnati, OH 45237-0507, USA.
Biochim Biophys Acta. 2007 Nov;1771(11):1372-9. doi: 10.1016/j.bbalip.2007.09.002. Epub 2007 Sep 26.
The requirement for cholesterol is greater in developing tissues (fetus, placenta, and yolk sac) as compared to adult tissues. Here, we compared cholesterol-induced suppression of sterol synthesis rates in the adult liver to the fetal liver, fetal body, placenta, and yolk sac of the Golden Syrian hamster. Sterol synthesis rates were suppressed maximally in non-pregnant adult livers when cholesterol concentrations were increased. In contrast, sterol synthesis rates were suppressed only marginally in fetal livers, fetal bodies, placentas, and yolk sacs when cholesterol concentrations were increased. To begin to elucidate the mechanism responsible for the blunted response of sterol synthesis rates in fetal tissues to exogenous cholesterol, the ratio of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) to Insig-1 was measured in these same tissues since the ratio of SCAP to the Insigs can impact SREBP processing. The fetal tissues had anywhere from a 2- to 6-fold greater ratio of SCAP to Insig-1 than did the adult liver, suggesting constitutive processing of the SREBPs. As expected, the level of mature, nuclear SREBP-2 was not different in the fetal tissues with different levels of cholesterol whereas it was different in adult livers. These findings indicate that the suppression of sterol synthesis to exogenous sterol is blunted in developing tissues and the lack of response appears to be mediated at least partly through relative levels of Insigs and SCAP.
与成体组织相比,发育中的组织(胎儿、胎盘和卵黄囊)对胆固醇的需求量更大。在此,我们比较了胆固醇诱导的叙利亚金黄地鼠成体肝脏、胎儿肝脏、胎儿身体、胎盘和卵黄囊中甾醇合成速率的抑制情况。当胆固醇浓度升高时,非妊娠成体肝脏中的甾醇合成速率受到最大程度的抑制。相比之下,当胆固醇浓度升高时,胎儿肝脏、胎儿身体、胎盘和卵黄囊中的甾醇合成速率仅受到轻微抑制。为了开始阐明胎儿组织中甾醇合成速率对外源胆固醇反应迟钝的机制,我们在这些相同的组织中测量了甾醇调节元件结合蛋白(SREBP)裂解激活蛋白(SCAP)与Insig-1的比值,因为SCAP与Insig的比值会影响SREBP的加工过程。胎儿组织中SCAP与Insig-1的比值比成体肝脏高2至6倍,这表明SREBPs存在组成型加工。正如预期的那样,不同胆固醇水平的胎儿组织中成熟核SREBP-2的水平没有差异,而成体肝脏中则有差异。这些发现表明,发育中的组织对外源甾醇的甾醇合成抑制作用减弱,这种无反应现象似乎至少部分是通过Insig和SCAP的相对水平介导的。